Collateral circulation to tissues can be stimulated in two independent ways: 1) the formation of new blood vessels through angiogenesis and 2) the enhancement in function of preexisting blood vessels (Fernandez et al., J Lab. Clin. Med. 105:141-145 (1985)).
Angiogenesis is the process by which new blood vessels are formed from existing capillaries. (U.S. Pat. No. 5,318,957, incorporated by reference herein in its entirety.) Angiogenesis plays an important role in such widely divergent biological conditions as embryonic development, tumor growth, wound healing, and chronic inflammatory disease. (Folkman et al., Science 235:442-447 (1987))
Capillaries are composed almost entirely of endothelial cells. Angiogenesis comprises a cascade of events, including protease secretion by endothelial cells, degradation of the basement membrane, migration through the surrounding matrix, proliferation, alignment, differentiation into tube-like structures, and synthesis of a new basement membrane. (U.S. Pat. No. 5,318,957)
Several angiogenic agents with different properties and mechanisms of action are well known in the art, including acidic and basic fibroblast growth factor, transforming growth factor alpha and beta, tumor necrosis factor, platelet-derived growth factor, vascular endothelial growth factor, angiogenin, and haptoglobin. (U.S. Pat. No. 5,318,957) However, the therapeutic applicability of some of these compounds is limited by their potent pleiotropic effects on various cell types. Thus, there remains a need in the art for angiogenic agents with more general applicability.
Very few therapies have been demonstrated to increase collateral circulation by S enhancing the function of existing blood vessels. In an isolated case, U.S. Pat. No. 4,296,100 discloses animal experiments wherein bovine fibroblast growth factor (FGF) was injected into the heart to distribute the desired amount of FGF over the area of the heart to be treated. This treatment was given as close to the time the heart attack as possible in order to control damage, possibly by improving collateral circulation, although the exact mechanism is unknown. The experiments showed that a one time treatment could reduce infarct size (area that will scar or remain permanently damaged) in the test animal to one quarter the size of the control (non-treated) hearts. Histological studies did not show a significant increase in capillary areas in the hearts as a result of such treatment with FGF.
Congestive heart failure is the leading cause of cardiovascular mortality (Tyagi, J. Cell Biochem. 65:388-394. (1997), and is caused by cardiac remodeling that leads to an enlargement of the heart following a myocardial infarction (Pfeffer, Am. J.Cardiol. 68:17D-25D (1991)). There is a strong correlation between long term morbidity from congestive heart failure and the degree of post-infarct remodeling. As little as a 35% increase in the volume of the heart in the months following infarction leads to an increase in mortality by a factor of 3-4 (Hammermeister et al., Circulation 59:421-435 (1979)). Therefore, therapies that attenuate cardiac remodeling following myocardial infarction are needed to prevent the development of congestive heart disease.
The loss of blood flow to the ischemic tissue is the primary factor in causing cardiac remodeling. Studies show that there is major cardiac remodeling following a myocardial infarction if the infarct-related artery is totally occluded (Kim and Braunwald, Circulation 88:2426-2436 (1993)). However, cardiac remodeling can be minimized if blood flow can be restored to the ischemic tissue. In addition, the earlier blood flow is restored the more cardiac remodelling can be attenuated (Hochman et al., Circulation 75:299-306 (1987); Bonaduce et al., J.Am. Coll. Cardiol 16:1561-1568 (1990)). Therefore, treatments aimed at quickly restoring blood flow following myocardial infarction can minimize cardiac remodeling and the development of congestive heart disease.
Chemical therapies are currently one of the most useful treatments for restoring blood flow to ischemic tissue following myocardial infarction. Thrombolytic therapies are based on clearing the occluded coronary artery in order to restore blood flow (U.S. Pat. No. 5,589,173). In addition to clearing the occluded coronary artery, the presence of a collateral blood supply can minimize the effect of cardiac remodeling. Therefore, chemical therapies directed at stimulating collateral circulation could minimize cardiac remodeling following myocardial infarction. However, there are currently few materials available for stimulating collateral blood flow.
Based on the above, there remains a need for the development of methods to increase blood flow to ischemic tissue in general, and a particular need for increasing blood flow to the heart following a myocardial infarction.
The present invention provides improved methods and kits to increase blood flow to ischemic tissue comprising the administration of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AI) analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists.